7. Project Summary/Abstract Down syndrome (DS) is the major cause of intellectual disability in humans and it is estimated there are over 300,000 individuals with this genetic disorder in the United States. Virtually all DS individuals have sufficient neuropathology for a diagnosis of Alzheimer disease (AD) in their 40th year. However, dementia may not develop until up to a decade later and some people remain cognitively intact. We hypothesize that mTOR signaling is a key component to aging in DS and may be targeted with an appropriate intervention. First, we will compare brain samples from people with DS over a wide range of ages to controls for changes in the mTOR pathway and downstream sequelae. Second, we will isolate exosomes from plasma samples from a cohort of people with DS that are being followed longitudinally to measure mTOR associated pathways and link these changes to cognitive decline and brain magnetic spectroscopy. These studies have the potential to identify novel biomarkers and clinical outcome measures for AD in people with DS. Identifying a role for the mTOR pathway in the pathogenesis of AD in DS may provide novel targets for a preventative approach to slow or halt the development of AD neuropathology and significantly improve the quality of life of DS individuals, as well as provides insights into AD itself.